Presentation is loading. Please wait.

Presentation is loading. Please wait.

The Journal of Thoracic and Cardiovascular Surgery

Published byKellie Chambers Modified over 5 years ago

Similar presentations

Presentation on theme: "The Journal of Thoracic and Cardiovascular Surgery"— Presentation transcript:

1 The Journal of Thoracic and Cardiovascular Surgery
The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high- mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway  Yikui Tian, MD, Eric J. Charles, MD, Zhen Yan, MD, Di Wu, MS, Brent A. French, PhD, Irving L. Kron, MD, Zequan Yang, MD  The Journal of Thoracic and Cardiovascular Surgery  DOI: /j.jtcvs Copyright © Terms and Conditions

2 The Journal of Thoracic and Cardiovascular Surgery DOI: (10. 1016/j
The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

3 Figure 1 A, Role of high-mobility group box 1 (HMGB1) or cell-free DNA (cfDNA) in myocardial ischemia-reperfusion injury (IRI). C57BL/6 mice underwent 40 minutes of ischemia and 60 minutes of reperfusion. Phatho blue (Heucotech, Fairless Hill, Pa) was used to stain the heart for delineation of infarct size (% of risk region), ischemic risk region (% of left ventricle). Anti-HMGB1 monoclonal antibody at a dose of 1 μg/g mouse weight or dioxyribonuclease I (DNase I) at a dose of 30 mU/g mouse weight administered 5 minutes before the onset of reperfusion. B, Effect of cfDNA depletion on plasma HMGB1. C, Effect of protein depletion on plasma cfDNA. NS, Not significant; PBS, phosphate buffered saline. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

4 Figure 2 Levels of free high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA) in myocardial tissue during ischemia/reperfusion (I/R) injury. C57BL/6 mice underwent either sham thoracotomy or I/R. Sytox green (Thermo Fisher, Waltham, Mass) was injected via intravenous bolus at a dose of 50 μL 1 mM 1 minute before reperfusion. The heart was harvested after injection in sham mice, and 5 minutes, 15 minutes, or 30 minutes following reperfusion. The left ventricle was cut into nonischemic posterior wall and ischemic anterior wall. A, Fluorescence of left ventricle anterior and posterior walls imaged under IVIS Lumina Imaging System (PerkinElmer, Akron, Ohio). B, Levels of cfDNA in the homogenates of the left ventricle anterior and posterior wall were measured using photometer. C, cfDNA was extracted from the left ventricle posterior and anterior walls, respectively, in sham, 40′/5′, and 40′/15′ hearts. The cfDNA was quantitatively measured using Nanodrop 2000 Spectrophotometer (Thermo Fisher Scientific, Waltham, Mass). The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

5 Figure 3 Level of free high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA) in coronary perfusate and plasma during ischemia-reperfusion injury (IRI). Left column, Cardiac coronary perfusate was obtained by antegrade perfusing of the heart via catheter through the ascending aorta. In the perfusate, the level of HMGB1 was measured by Western blot and the level of cfDNA was measured using Sytox Green (Thermo Fisher, Waltham, Mass) and photometry. Right column, The blood sample was obtained during IR by puncturing the right ventricle. The plasma level of HMGB1 was measured by Western blot and the level of cfDNA was measured using Sytox green and photometry. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

6 Figure 4 Role of exogenous cardiac coronary perfusate in exacerbating myocardial infarct size. Perfusate acquired from 10′/0′ or 40′/0′ donor hearts was administered via intravenous bolus 5 minutes before reperfusion at a dose of 2 μL/g recipient mouse. The recipient mice underwent 20′/60′ ischemia-reperfusion (IR). SPLX, Splenectomy 5 minutes before occlusion of left coronary artery. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

7 Figure 5 Role of exogenous plasma in exacerbating myocardial infarct size. A, Plasma acquired from 10′/5′ or 40′/5′ donor C57BL/6 mice was administered intravenous bolus 5 minutes before reperfusion at a dose of 2 μL/g recipient mouse. The recipient mice underwent 20′/60′ ischemia-reperfusion (IR). Immunoprecipitation was used to deplete high-mobility group box 1 (HMGB1) in the donor plasma; deoxyribonuclease I (DNase I) was used to deplete cell-free DNA in the donor plasma at a dose of 1 mU/μL donor plasma. Upper portion, Representative triphenyltetrazolium chloride/Phthalo blue staining of the middle left ventricular slice. Top, the ischemic area (red), infarct area (yellow), and nonischemic area (blue) are drawn and included area can be calculated. B, Level of cell-free DNA in the 40′/5′ plasma with different treatments using Sytox Green (Thermo Fisher, Waltham, Mass). (Results of proteinase K-treated plasma are also reported in Figure 1, C). RAGE KO, Receptor for advanced glycation end products knockout; TLR9 KO, Toll-like receptor 9 knockout. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

8 Figure 6 Splenic tissue level of interleukin (IL)-1β protein and messenger RNA. Spleen was harvested from sham, 10′/30′, and 40′/30′ mice and homogenized. IL-1β protein and messenger RNA were evaluated by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction, respectively. PBS, Phosphate buffered saline; RTC-PCR, reverse transcriptase-polymerase chain reaction. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

9 Figure 7 Role of exogenous recombinant high-mobility group box 1 (rHMGB1) and mitochondrial DNA (mtDNA) in exacerbating myocardial infarct size. C57BL/6 mice and receptor for advanced glycation end products knockout (RAGE KO) mice underwent 20′/60′ ischemia reperfusion (IR) injury and were treated upon reperfusion with either mouse rHMGB1 at a dose of 0.1 μg/g mouse weight and/or mouse mtDNA at a dose of 0.5 μg/g mouse weight. A, Combined treatments 5 minutes before reperfusion exacerbated infarct size in C57BL/6 mice but not in RAGE KO or splenectomized C57BL/6 mice. B, 30 minutes after treatment in mice without IR injury, combined treatments increased splenic tissue DNA level in C57BL/6 mice more significantly than combined treatment in RAGE KO mice or the individual treatment with either rHMGB1 or mtDNA in C57BL/6 mice. C, 30 minutes after treatment in mice without IR injury, the plasma level of cfDNA was similar among the 5 groups. SPLX, Splenectomy 5 minutes before occlusion of left coronary artery; PBS, phosphate buffered saline. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

10 Figure 8 Schematic mechanism of the free high-mobility group box 1 (HMGB1) and cell-free DNA (cfDNA) complex in acute myocardial ischemia-reperfusion injury. DNase I, Deoxyribonuclease I; RAGE, receptor for advanced glycation end products; TLR9, Toll-like receptor 9. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

11 Figure E1 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; DNase I, deoxyribonuclease I; anti-HMGB1, anti-high-mobility group box 1. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

12 Figure E2 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; SPLX, splenectomy. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

13 Figure E3 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; B6, C57BL/6; HMGB1, high-mobility group box 1; DNase I, deoxyribonuclease I; RAGE KO, receptor for advanced glycation end products knockout; TLR9 KO, Toll-like receptor 9 knockout. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

14 Figure E4 Risk regions were similar among all groups. LV, Left ventricle; NS, not significant; PBS, phosphate buffered saline; rHMGB1, recombinant high-mobility group box 1; mtDNA, mitochondrial DNA; SPLX, splenectomy; RAGE KO, receptor for advanced glycation end products knockout. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

15 Figure E5 Intravenous injection of deoxyribonuclease I (DNase I) at 30 mU/g reduced myocardial infarct size after 40′/60′ ischemia/reperfusion. Lower dose of DNase I (2 mU/g) had no infarct-sparing effect. NS, not significant. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

16 Figure E6 Plasma cell-free DNA (cfDNA) significantly increased after exogenous mitrochondrial DNA injection (0.5 μg/g) at 5 minutes. At 30 minutes, plasma cfDNA decreased back to the normal level. PBS, Phosphate buffered saline. The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

17 Schematic mechanism of the HMGB1-cfDNA complex in acute myocardial ischemia/reperfusion injury.
The Journal of Thoracic and Cardiovascular Surgery DOI: ( /j.jtcvs ) Copyright © Terms and Conditions

Download ppt "The Journal of Thoracic and Cardiovascular Surgery"

Similar presentations

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMBG1 and.

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMBG1 and.
MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice  Shrikant R. Mulay, Dana Thomasova, Mi Ryu,

MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice  Shrikant R. Mulay, Dana Thomasova, Mi Ryu,
Induction of Shock After Intravenous Injection of Adenovirus Vectors: A Critical Role for Platelet-activating Factor  Zhili Xu, Jeffrey S. Smith, Jie.

Induction of Shock After Intravenous Injection of Adenovirus Vectors: A Critical Role for Platelet-activating Factor  Zhili Xu, Jeffrey S. Smith, Jie.
Inhibition of Na-K-Cl cotransporter isoform 1 reduces lung injury induced by ischemia– reperfusion  Chou-Chin Lan, MD, PhD, Chung-Kan Peng, MD, PhD, Shih-En.

Inhibition of Na-K-Cl cotransporter isoform 1 reduces lung injury induced by ischemia– reperfusion  Chou-Chin Lan, MD, PhD, Chung-Kan Peng, MD, PhD, Shih-En.
High mobility group box 1 promotes endothelial cell angiogenic behavior in vitro and improves muscle perfusion in vivo in response to ischemic injury 

High mobility group box 1 promotes endothelial cell angiogenic behavior in vitro and improves muscle perfusion in vivo in response to ischemic injury 
Induction by left ventricular overload and left ventricular failure of the human Jumonji gene (JARID2) encoding a protein that regulates transcription.

Induction by left ventricular overload and left ventricular failure of the human Jumonji gene (JARID2) encoding a protein that regulates transcription.
Reduction of systolic and diastolic dysfunction by retrograde coronary sinus perfusion during off-pump coronary surgery  Manuel Castellá, MD, Gerald D.

Reduction of systolic and diastolic dysfunction by retrograde coronary sinus perfusion during off-pump coronary surgery  Manuel Castellá, MD, Gerald D.
High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells  Bo Wang, PhD, Fei Li, MD, Chao Zhang, PhD,

High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells  Bo Wang, PhD, Fei Li, MD, Chao Zhang, PhD,
Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps  Rahmi Oklu,

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps  Rahmi Oklu,
Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression  Rong Yin, MD, Jiaquan Zhu,

Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression  Rong Yin, MD, Jiaquan Zhu,
Ulka Sachdev, MD, Xiangdong Cui, MS, Edith Tzeng, MD 

Ulka Sachdev, MD, Xiangdong Cui, MS, Edith Tzeng, MD 
Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion  Marshall T. Bell, MD,

Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion  Marshall T. Bell, MD,
Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo  Jessica A. Yu, MD, David Mauchley, MD, Howard Li, MD, Xianzhong.

Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo  Jessica A. Yu, MD, David Mauchley, MD, Howard Li, MD, Xianzhong.
Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells  Stephen L. Hendry, MD, Koen E.A.

Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells  Stephen L. Hendry, MD, Koen E.A.
An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb.

An engineered vascular endothelial growth factor-activating transcription factor induces therapeutic angiogenesis in ApoE knockout mice with hindlimb.
Mary E. Huerter, MD, MA, Ashish K

Mary E. Huerter, MD, MA, Ashish K
Annexin V homodimer protects against ischemia reperfusion–induced acute lung injury in lung transplantation  Kohei Hashimoto, MD, Hyunhee Kim, MSc, Hisashi.

Annexin V homodimer protects against ischemia reperfusion–induced acute lung injury in lung transplantation  Kohei Hashimoto, MD, Hyunhee Kim, MSc, Hisashi.
A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion.

A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion.
Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury  Albert J Chong, MD, Timothy H Pohlman, MD, Craig R Hampton, MD, Akira Shimamoto,

Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury  Albert J Chong, MD, Timothy H Pohlman, MD, Craig R Hampton, MD, Akira Shimamoto,
Li-Wen Lai, Kim-Chong Yong, Yeong-Hau H. Lien  Kidney International 

Li-Wen Lai, Kim-Chong Yong, Yeong-Hau H. Lien  Kidney International 

Similar presentations

Ads by Google